Rett syndrome (RTT, MIM 312750), an X-linked disorder, is a leading cause of mental retardation and autistic features in females. Affected girls achieve the expected physical and intellectual milestones until some point between 6 and 18 months of life, when they lose whatever language skills have acquired, their cranial growth slows, and they develop ataxia, gait apraxia, seizures, breathing dysrhythmias, and autistic behavior. Our laboratory recently found that mutations in the gene encoding methyl- CpG-binding protein 2 (MeCP2) cause Rett syndrome (RTT). We also found that the phenotypic consequences of MECP2 mutations vary from normal or mild learning disability to classic RTT, depending on the pattern of X chromosome inactivation (XCI), MeCP2 mediates transcriptional silencing by binding 5 methyl-cytosines with its methyl- binding domain (MBD) while the transcriptional repressor domain (TRD) recruits a co-repressor a complex containing Sin3A and histone deacetylase. We thus propose that the RTT phenotype is caused by altered expression of genes that are key for normal neuronal development, and that mutations in MECP2 are responsible for some cases of autism, mental retardation or learning disability. The overall goal of this project is to test these main hypotheses and to investigate the mechanism or learning disability. The overall goal of this project is to test these main hypotheses and to investigate the mechanism of pathogenesis in RTT. To define the full phenotypic spectrum of MECP2 mutations we will screen a large number (approximately 800-1,000) of females who have a diagnosis of learning disability, mental retardation, autism, and atypical or classic RTT for mutations in this gene. To carry out pathogenesis studies we will first generate and characterize mouse models of RTT using both gene targeting and transgenic approaches. To identify genes whose proper expression depends on normal MeCP2 function, we will use microarray expression analysis to compare gene expression in mutant and wild-type mice at different times during nervous system development. Lastly, we will investigate possible therapies (such as treatment with methyl group donors, agents which can modulate pathways we uncover through pathogenesis studies or supportive therapies) in mice to determine the effects of early intervention on outcome. These studies should provide insight about the pathogenesis of RTT as well as common disabling neurodevelopmental disorders such as autism and non-syndromic mental retardation and could lead to effective therapy in the future.